Abstract
Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Several proteins and polysaccharide capsule have recently been implicated in the virulence of and protective immunity against Streptococcus pneumonia. Pneumococcal surface protein A (PspA) is highly conserved among S. pneumonia strains, inhibits complement activation, binds lactoferrin, elicits protective systemic immunity against pneumococcal infection, and is necessary for full pneumococcal virulence. Identification of PspA peptides that optimally bind human leukocyte antigen (HLA) would greatly contribute to global vaccine efforts, but this is hindered by the multitude of HLA polymorphisms. Here, we have used an experimental data set of 54 PspA peptides and in silico methods to predict peptide binding to HLA and murine major histocompatibility complex (MHC) class II. We also characterized spleen- and cervical lymph node (CLN)-derived helper T lymphocyte (HTL) cytokine responses to these peptides after S. pneumonia strain EF3030-challenge in mice. Individual, yet overlapping peptides, 15 amino acids in length revealed residues 199 to 246 of PspA (PspA199–246) consistently caused the greatest IFN-γ, IL-2, IL-5 and proliferation as well as moderate IL-10 and IL-4 responses by ex vivo stimulated splenic and CLN CD4+ T cells isolated from S. pneumonia strain EF3030-challeged F1 (B6×BALB/c) mice. IEDB, RANKPEP, SVMHC, MHCPred, and SYFPEITHI in silico analysis tools revealed peptides in PspA199–246 also interact with a broad range of HLA-DR, -DQ, and -DP allelles. These data suggest that predicted MHC class II-peptide binding affinities do not always correlate with T helper (Th) cytokine or proliferative responses to PspA peptides, but when used together with in vivo validation can be a useful tool to choose candidate pneumococcal HTL epitopes.
Highlights
Pneumococcal pneumonia is the most common cause of childhood deaths in the developing world and among the top ten causes of death in aged populations worldwide; recently, antibiotic-resistant S. pneumonia strains have emerged [1,2,3,4]
helper T lymphocyte (HTL) epitopes contained in synthetic peptide vaccines must: (i) match those naturally presented to the immune system during infection, (ii) be recognized by the majority of the human population, and (iii) induce an appropriate effector immune response to eliminate the pathogen of interest
T cells are crucial for generating an efficient immune response following recognition of foreign antigen in the context of major histocompatibility complex (MHC)
Summary
Pneumococcal pneumonia is the most common cause of childhood deaths in the developing world and among the top ten causes of death in aged populations worldwide; recently, antibiotic-resistant S. pneumonia strains have emerged [1,2,3,4] Vaccines against these strains are greatly needed. A central event in the adaptive immune response to invasive microorganisms is the specific recognition of processed antigens bound to the peptide-binding region of MHC class II molecules on the surface of antigen-presenting cells. These peptide antigens are subsequently detected by the T cell receptor (TCR) of CD4+ T cells, which proliferate, secrete cytokines, and differentiate into antigen-specific Th effector cells. It is unlikely that T cells from genetically distinct populations would recognize, and respond to a single peptide epitope
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